Functional analyses of VCP protein in neuronal cell death

VCP蛋白在神经细胞死亡中的功能分析

基本信息

批准号：
16390092
负责人：
KAKIZUKA Akira
金额：
$ 9.66万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390092/
关键词：
VCP neuronal cell death amino acid modification oxidation protein aggregates AAA ATPase polyglutmamine 神経変性疾患ミスセンス変異 IBMPFD 凝集体形成

项目摘要

Recent molecular analyses on human neurodegenerative disorders have revealed several common features such as accumulation of abnormal protein aggregates, cytoplasmic vacuolizations, neuronal cell death etc. We have analyzed the molecular bases of such disorders especially polyglutamine diseases, and have identified VCP protein, an AAA class ATPase, as a candidate for a sensor for the accumulation of abnormal proteins as well as for a mediator of cell death. Namely, 1)VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease, 2)the expression of ATPase activity-negative VCP in nueoronal cells induces ER-derived vacuoles and cell death, 3)several amino acids in VCP are modified by phoshprylations, acetylations and oxidations, 4)such modification can change VCP ATPase activities and its intra cellular localization, 5)especially, oxidized VCP at the 522 cysteine loses its ATPase activities, 6)depending upon the levels of soluble aggregates-prone proteins, VCP can modulate the aggregate formation, indicating dual VCP functions as an aggregate formase and an unfoldase. Further molecular analyses on VCP would lead to clues for further understanding as well as for novel treatments of neurodegenerative disorders such as polyglutamine diseases and Parkinson disease.

最近对人类神经退行性疾病的分子分析揭示了一些常见特征，例如异常蛋白质聚集体的积累、细胞质空泡化、神经元细胞死亡等。我们分析了此类疾病尤其是聚谷氨酰胺疾病的分子基础，并鉴定了 VCP 蛋白（AAA 类） ATP酶，作为异常蛋白质积累传感器以及细胞死亡介质的候选者。即，1) VCP 与聚谷氨酰胺聚集体和其他蛋白质聚集体（例如帕金森病中的路易体）共定位，2) 神经元细胞中 ATP 酶活性阴性 VCP 的表达诱导 ER 衍生的空泡和细胞死亡，3) 几种氨基酸VCP中的磷酸化、乙酰化和氧化修饰，4)此类修饰可以改变VCP ATP酶活性及其细胞内定位， 5) 特别是，522 半胱氨酸处的氧化 VCP 失去了 ATP 酶活性，6) 根据可溶性聚集倾向蛋白的水平，VCP 可以调节聚集体形成，表明 VCP 具有聚集形成酶和解折叠酶的双重功能。对 VCP 的进一步分子分析将为进一步了解以及神经退行性疾病（如多谷氨酰胺疾病和帕金森病）的新治疗提供线索。